Insulin is a blood glucose level-controlling hormone secreted by the pancreas, and serves to transport excess glucose in the blood to cells, thereby supplying an energy source and maintaining a normal glucose level. However, diabetic patients cannot maintain normal insulin functions due to insulin deficiency, insulin resistance, and loss of beta-cell function. As a result, diabetic patients cannot utilize the glucose in the blood as an energy source, but show symptoms of hyperglycemia with a high glucose level and excrete the glucose in the urine, which cause of various complications. Accordingly, those diabetic patients who have abnormalities in insulin secretion (type I) or insulin resistance (type II) essentially require insulin treatment, and by insulin administration, they can keep their blood glucose levels normal.
Human insulin consists of two polypeptide chains, i.e., the A-chain and the B-chain, which respectively include 21- and 30 amino acids, connected with each other by two disulfide bonds. Since insulin has an extremely short in vivo half-life, as is the case with other protein and peptide hormones, it is unable to show a sustained therapeutic effect, and thus has a problem in that it must be administered continuously and repeatedly to exert its effect. The frequent administration of insulin causes severe pain and discomfort to patients, and thus there is a need to improve the administration from the aspects of patient compliance, safety, and convenience.
Accordingly, studies have focused on the development of various protein formulations, chemical conjugates, etc. for improving the therapeutic effects as well as the quality of patients' lives by reducing the frequency of administration through the increase of the in vivo half-life of these protein drugs such as insulin.
Insulin is known to remove blood glucose by binding to insulin receptors and the effect of insulin can be controlled by altering the sequence of native insulin. The in vivo effect of insulin can be controlled by substitution of amino acid(s) of insulin with different amino acid(s) or by deletion of specific amino acid(s) of insulin. Since insulin derivatives with high activity can exert effects equivalent to or better than those of native insulin, even in a small amount, they may thus be very desirable from the therapeutic point of view. In particular, amino acid substitutions in the A-chain and/or the B-chain contained in insulin have been broadly studied from the aspect of a pharmacokinetic effect of insulin action after subcutaneous injection.
Under these circumstances, the present inventors have intensively studied to improve the effect of insulin action, and as a result, they have discovered that the insulin analogs with modification(s) in particular amino acid residue(s) in the A-chain and/or the B-chain of insulin exhibit a markedly improved in vitro effect compared to that of native insulin, and that they can thus be effectively used for treating diabetes, thereby completing the present invention.